More than a century of investigation has failed to elucidate the mechanism(s) which produce the respiratory responses to exercise. The receptor sites mediating these responses have been variously ascribed to the heart, lungs, peripheral chemoreceptors and exercising muscles. Elimination of individual mechanisms proposed to mediate these responses have failed to provide conclusive evidence, perhaps due to redundant control systems. We propose to eliminate neural feedback from multiple receptor sites and determine the effect of those interventions on the ventilatory responses to treadmill exercise in conscious dogs. Afferent input from the heart, lungs, aortic arch and carotid sinus region, and the exercising muscles will be abolished in various combinations and conjointly. The primary focus of the studies will be on the blood gas responses during the transition from rest to exercise and from one exercise workload to the next. A significant alteration in the responses to exercise following a particular intervention will be interpreted as indicating a role for the involved receptor sites in the respiratory drive under those conditions. The salient features of this proposal are: 1) application of a new surgical technique for total cardiopulmonary denervation, 2) epidural administration of bupivacaine to produce differential sensory and motor blockade, 3) intrathecal administration of morphine to block a specific group of muscle afferents, 4) employing conscious animals rather than anesthetized animal preparations and 5) careful experimentation employing rigid protocols designed to allow precise quantitation of results. The results of the proposed studies should provide important new information on the relative importance of peripheral feedback in respiratory control during exercise.